Abstract 1588: Transformation of primary human fallopian tube secretory epithelial cells: A cell of origin for high-grade serous ovarian carcinoma

Abstract

Abstract High-grade serous ovarian carcinoma (HGSOC) is a lethal disease for which improved screening and treatment strategies are urgently required. Progress in these areas has been impeded by our poor understanding of HGSOC pathogenesis. The vast majority of ovarian cancer research is been based on the hypothesis that HGSOC develops from ovarian surface epithelial cells. However, recent studies suggest that > 50% of high-grade serous carcinomas involving the ovary likely arose from secretory cells of the fallopian tube epithelium. Consequently, current ovarian-based experimental models of HGSOC are inadequate in representing the full spectrum of the disease. The aim of our study was to develop the first experimental model of fallopian tube secretory epithelial cell (FTSEC) transformation and to use this model to answer three basic questions: 1) Can FTSECs be transformed in vitro?, 2) What genetic alterations are capable of transforming FTSECs?, and 3) Do transformed FTSECs give rise to high-grade serous carcinomas? To this end, we isolated primary human FTSECs from fresh samples of normal fallopian tube fimbriae and immortalized them via transduction with hTERT and SV40 TAg. Immortal FTSECs were transformed by either H-RasV12 or c-Myc expression, resulting in accelerated proliferation, enhanced clonogenicity, anchorage-independent growth, and tumor formation in immunodeficient mice. When SV40 TAg was replaced with equivalent non-viral genetic alterations (sh-p53, CDK4R24C, and sh-PP2A-B56γ), FTSECs remained susceptible to c-Myc-induced transformation and tumorigenesis. These results indicate that hTERT expression plus combined dysfunction of the p53, Rb, and PP2A tumor suppressor pathways is sufficient to support c-Myc-mediated transformation. Importantly, all of the transformed FTSECs in our study produced high-grade serous tumors with Müllerian and epithelial characteristics. Moreover, these tumors were grossly, histologically, and immunophenotypically consistent with human HGSOC. The genetic elements employed by our model represent the most common genomic alterations in human HGSOC – namely, TP53 mutation, RB1 dysfunction, and c-MYC amplification – and are therefore appropriate for modeling this disease. In summary, we have presented the first proof-of-principle evidence that FTSECs can be transformed into high-grade serous carcinomas resembling HGSOC. Our FTSEC transformation model provides a novel framework for assessing the transformative effects of specific genetic alterations on primary FTSECs and thus determining what role they may play in the pathogenesis of HGSOC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1588. doi:10.1158/1538-7445.AM2011-1588